Prostate cancer (PCa) is the most common cancer in American men, contributing to 220,800 new cases and 27,540 deaths in 2015 (Siegel, et al., CA Cancer J Clin, 65: 5-29 (2015)). Current therapies, although temporarily reducing cancer-related complications, do not have significant survival benefits. Particularly, single-agent treatment only exhibits limited activity in clinical settings, which may be attributed to the intrinsic and complex heterogeneity of a tumor (Meacham, et al., Nature, 501: 328-337 (2013)). Indeed, abnormalities in multiple tumor suppressors and oncogenes have been identified in PCa3, which may account for the failure of most targeted therapies that selectively block a single oncogenic molecule or signaling pathway.
Activation of EGFR signaling has been shown to increase cancer cell proliferation, enhance tumor vascularization and promote metastasis (De Luca, et al., J Cell Physiol, 214: 559-567 (2008); Howe, et al., Cancer Prev Res (Phila), 4: 1149-1157 (2011)). EGFR overexpression is associated with castration-resistant and high-risk PCa, as well as PCa bone metastasis (Schlomm, et al, Clin Cancer Res, 13: 6579-6584 (2007); Di Lorenzo, et al., Clin Cancer Res, 8: 3438-3444 (2002); Chang, et al., Cancer Res, 75: 3077-3086 (2015); Traish, et al., British Journal of Cancer, 101: 1949-1956 (2009)). EGFR inhibitors (e.g. erlotinib, gefitinib) have been used to treat prostate, pancreatic, lung, colorectal and head and neck cancers (Cataldo, et al., N Engl J Med, 364: 947-955 (2011); Moore, et al., J Clin Oncol, 25: 1960-1966 (2007)). However, the benefit of EGFR inhibitors is temporary and can be quickly counteracted by acquired resistance (Chong, et al., Nat Med, 19: 1389-1400 (2013)). Combination treatment, on the other hand, may restore the sensitivity of tumors to EGFR inhibitors. For example, the combined use of anti-MEK and anti-EGFR inhibitors can overcome the resistance of colorectal cancer13, and the combination of anti-EGFR and anti-VEGF agents have shown success and some have been approved for the clinical trials (Ciardiello, et al., Annals of Oncology, 17: Vii109-Vii114 (2006)).
Survivin, a member of the inhibitor of apoptosis (IAP) protein family (Lens, et al., Curr Opin Cell Biol, 18: 616-622 (2006)), plays a pivotal role in the progression of PCa and other solid tumors. Its overexpression has been correlated to recurrence, metastasis and therapeutic resistance (Altieri, et al., Cancer Lett, 332: 225-228 (2013); Stauber, et al., Cancer Res, 67: 5999-6002 (2007); Zhang, et al., Oncogene, 24: 2474-2482 (2005)). Survivin has been actively pursued as an ideal target for cancer treatment. However, the portfolio of efficient survivin antagonists is small. Currently available inhibitors of survivin (such as YM155) have modest activity and are associated with side effects (Rauch, et al., Biochimica Et Biophysica Acta-Reviews on Cancer, 1845: 202-220 (2014)). The lack of survivin-directed antagonists also reflects the limitation of current drug design, since only those molecules expressed on cell surface or having enzymatic activity are considered to be druggable. It remains challenging to discover small molecule inhibitors against cytoplasmic proteins (such as survivin).
Heterogeneity is an intrinsic characteristic of human cancer, particularly at advanced stages. Combination therapy to target several oncogenic pathways simultaneously, therefore, may have better efficacy in retarding or eradicating tumors. Small molecule drug combination usually shows some efficacy initially, but reaches a plateau with increased toxicity and quickly developed drug resistance. For example, although current kinase inhibitor combinations show efficacy and certain targeting, most kinase inhibitors tend to target multiple kinases (low specificity), and combinations of different kinases may more easily cause overlapping toxicities. Combinations of monoclonal antibodies are usually more specific but have limitations in antagonizing intracellular targets/signaling and high immunogenicity due to their membrane impermeability and recognition by host as foreign.
Therefore it is an object of the invention to provide compositions and methods for selectively targeting cells to inhibit gene expression.
It is another object to provide compositions and methods for selectively targeting virally infected cells to inhibit gene expression.
It is another object of the invention to provide compositions and methods for selective targeting cells to inhibit multiple genes in the cells.
It is still another object of the invention to provide compositions and methods for reducing tumor burden in a subject.
It is still another object of the invention to provide compositions and methods for treating cancer or viral infections.